Search for Registered TCM trials
169 registered TCM clinical trials on COVID–19 were initially identified from three registries. The majority (155, 91.7%) were registered in ChiCTR, the representative registry of China in the World Health Organization International Clinical Trial Registration Platform, accounting for 23.7% (155/653) of all trials on COVID–19 up to May 14. 10 trials (5.9%) were registered in ClinicalTrials.gov, and 2 (1.2%) in AMCTR. No records were found from other registries. Eight trials were excluded after screening the full text of protocols, of which Six (ChiCTR2000030118; ChiCTR2000030168; ChiCTR2000030478; ChiCTR2000030483; ChiCTR2000030762; ChiCTR2000030765) were cancelled by the investigator; four (ChiCTR2000030420 & ChiCTR2000030467; ChiCTR2000030382 & AMCTR-OCN–20000332) were duplicate registrations, and the more recently registered one was included. Therefore, 161 registered trials were finally included in this study. The lists of the 161 trials were shown in Supplementary Material.
Characteristics of registered TCM clinical trials
All of the registered TCM clinical trials were planned to be conducted in China, involving a total sample size of 58,501 (range: 20 to 20,000; average: 404; median: 132). The first protocol of a TCM clinical study (NCT04285190) on COVID–19 was registered on January 26, 2020, and the most recent was on May 9. The number of registrations on February 1 was the largest, up to 9. The number of newly confirmed cases has dropped significantly since February 17, with a total of 11,683 cases reported, accounting for 14.1% (11683/82918) of all cases; while during this period, 91 trials were registered, accounting for 56.5% (91/161) of all trials. Six trials (ChiCTR2000029433, ChiCTR2000029434, ChiCTR2000029479, ChiCTR2000030619, ChiCTR2000032717, and ChiCTR2000032767) have completed participant recruitment.
The trends of newly registered TCM trials and confirmed cases of COVID–19 from January 26 to May 14 are presented in Figure 1. The details on the characteristics of registered TCM clinical trials including study design, objectives, participants, and sample size, interventions, outcome measure, and current status are shown in Table 1.
Table 1 The characteristics of the registered trials
Items
|
Details
|
Number of trials
|
Percent (%)
|
Study type
|
Randomized controlled trials
|
94
|
58.4%
|
Controlled clinical trials
|
25
|
15.5%
|
Single-arm trials
|
18
|
11.2%
|
Real world clinical studies
|
10
|
6.2%
|
Retrospective studies
|
10
|
6.2%
|
Cross-sectional studies
|
4
|
2.5%
|
Objective
|
Prevention
|
12
|
7.5%
|
Treatment
|
114
|
70.8%
|
Rehabilitation
|
23
|
14.3%
|
TCM syndrome epidemiology
|
4
|
2.5%
|
Multi-objective
|
8
|
5.0%
|
Sample size
|
≤100
|
63
|
39.1%
|
101-300
|
65
|
40.4%
|
301-500
|
16
|
9.9%
|
501-1000
|
11
|
6.8%
|
>1000
|
6
|
3.7%
|
Participants (in 114 treatment trials)
|
Suspected cases*1
|
10
|
8.8%
|
Mild or moderate patients
|
55
|
48.2%
|
Severe patients
|
32
|
28.1%
|
Critical patients
|
3
|
2.6%
|
Confirmed patients (no details on severity)
|
39
|
34.2%
|
TCM Interventions
|
Chinese patent medicine
|
40
|
24.8%
|
Decoction or granule of fixed formulae
|
50
|
31.1%
|
Decoction or granule based on TCM syndrome differentiation
|
17
|
10.6%
|
Chinese herbal-derived injections
|
13
|
8.1%
|
TCM exercises (Qigong/Daoyin/Liuzijue/ Tai Chi/Baduancao)
|
12
|
7.5%
|
Moxibustion
|
5
|
3.1%
|
Acupuncture/acupoint stimulation
|
4
|
2.5%
|
TCM psychological intervention
|
1
|
0.6%
|
TCM interventions with no details
|
36
|
22.4%
|
Comparisons (in 157 interventional studies)
|
TCM plus WM vs WM
|
75
|
47.8%
|
Single arm
|
28
|
17.8%
|
Multiple comparisons
|
14
|
8.9%
|
TCM vs WM*2
|
10
|
6.4%
|
TCM vs no intervention (in preventive study)
|
11
|
7.0%
|
TCM plus WM vs Placebo plus WM
|
9
|
5.7%
|
TCM vs Placebo (in rehabilitation study)
|
7
|
4.5%
|
Others
|
3
|
1.9%
|
Recruitment status
|
Have not started recruiting
|
75
|
46.6%
|
Have started recruiting
|
78
|
48.4%
|
Completed
|
6
|
3.7%
|
Suspended
|
2
|
1.2%
|
Note: 1. Suspected case is defined as a patient with a history of epidemiology and clinical manifestations, yet to be confirmed by etiological or serological tests according to China’s guideline of COVID-19.3
2. TCM: traditional Chinese medicine; WM: western medicine, defined as conventional treatment according to China’s guideline of COVID-19, including symptomatic treatment, antiviral drugs, antibiotics, respiratory and circulatory support, etc.3
Registered Clinical trials and interventions worthy of attention
Trials of preventive interventions
12 registered trials are preventive studies, including six randomized controlled trials (RCTs), three controlled clinical trials (CCTs), two single-arm studies, and one retrospective study. Participants included the general population in two trials and high-risk populations in close contact with confirmed cases in ten trials. The sample sizes ranged from 80 to 20,000, with a total of 28766, average of 2398, and median of 550. Preventive interventions included six Chinese patent medicines, moxibustion, and herbal decoction. Among ten controlled studies, nine had no intervention in the control group and one used placebo. 58.3% (7/12) of trials reported the infection rate diagnosed by nucleic acid PCR test as the primary outcome.
Amongst the 12 trials, three therapies in five trials might be worthy of attention due to their previous clinical evidence and inclusion by relevant guidelines or expert consensus:
(1) Moxibustion was recommended by the China Association of Acupuncture-Moxibustion [11] and tested in two registered trials including one RCT (Registration number: AMCTR-IPR–20000326) and one case series study (ChiCTR2000030386). However, both are assessing relief in scores of emotion and symptom scale, rather than infection rate by nucleic acid PCR test as their primary outcome measurement.
(2) Huoxiang Zhengqi pill (藿香正气丸, HXZQ) was recommended in the guideline for COVID–19 (from the fourth version) issued by the National Health Commission of China for suspected cases under medical observation with fatigue and gastrointestinal discomfort symptoms [3]. Two RCTs (ChiCTR2000029602 and ChiCTR2000029479) tested HXZQ were planned to compare with health education and no intervention in high-risk populations or healthy people in the community. Both used the incidence of COVID–19 based on nucleic acid PCR test as the primary outcome, and the sample sizes were 600 and 20000 respectively. The study of ChiCTR2000029479 has been published in China Journal of Chinese Materia Medica on April 30, 2020, showing that the incidence rate of cold in TCM group combined use of HXZQ and another Chinese patent medicine (10627 cases) was significantly lower than that in non-intervention group (10972 cases) (0.02% versus 0.23%, P<0.001), no confirmed COVID–19 case occurred in either group [12].
(3) Jinye Baidu granule (金叶败毒颗粒, JYBD) was officially recommended for preventing COVID–19 in some provinces of China [4]. JYBD was developed by Tongji hospital, Huazhong University of Science and Technology, and had been used for preventing SARS in Tongji Hospital in 2003 [13]. Some experimental and clinical studies found that JYBD had an antiviral effect [14–16]. One retrospective single-arm study (ChiCTR2000029728) evaluated the preventive effect of JYBD for COVID–19.
The details of the above interventions and trials are shown in Table 2.
Table 2 Characteristics of TCM preventive interventions and trials worthy of attention
Intervention
|
Category
|
Trials
|
Rationality
|
Ingredients
|
Moxibustion
|
TCM external treatment
|
AMCTR-IPR-20000326
|
Included in guideline
|
Artemisiae Argyi Folium (Aiye)
|
Huoxiang zhengqi pill
|
Chinese patent medicine
|
ChiCTR2000029602
ChiCTR2000029479
|
Included in guideline
|
Pericarpium Arecae (Dafupi), Radix Angelicae Dahuricae (Baizhi), Caulis Perillae (Zisu), Poria (Fuling), Rhizoma Pinelliae Preparata (Banxiaqu), Atractylodis Macrocephalae Rhizoma (Baizhu), Pericarpium Citri Reticulatae (Chenpi), Cortex Magnoliae Officinalis (Houpo), Radix Platycodi (Jiegeng), Pogostemonis Herba (Huoxiang), Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle (Zhigancao), Rhizoma Zingiberis Recens (Shengjiang), Fructus Jujubae (Dazao)
|
Jinye baidu granule
|
Chinese patent medicine
|
ChiCTR2000029728
|
Used for preventing SARS
|
Lonicerae Japonicae Flos (Jinyinhua), Isatidis Folium (Daqingye), Taraxaci Herba (Pugongying), Houttuyniae Herba (Yuxingcao)
|
Table 3 Characteristics of TCM treatment interventions and trials worthy of attention
Intervention
|
Category
|
Trials
|
Rationality
|
Ingredients
|
Qingfei Paidu Decoction
|
New formula for COVID-19
|
ChiCTR2000030810, ChiCTR2000029778; ChiCTR2000030864; ChiCTR2000030883; ChiCTR2000030806;
ChiCTR2000032767
|
Included in guideline
|
Ephedrae Herba (Mahuang) Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle (Zhigancao), Armeniacae Semen (Xingren), Gypsum Fibrosum (Shengshigao), Cinnamomi Ramulus (Guizhi), Alismatis Rhizoma (Zexie), Polyporus (Zhuling), Atractylodis Macrocephalae Rhizoma (Baizhu), Poria (FulLing), Bupleuri Radix (Chaihu), Scutellariae Radix (Huangqin), Pinellinae Rhizoma Praeparatum (Jiangbanxia), Zingiberis Rhizoma recens (Shengjiang), Asteris Radix (Ziwan), Farfarae Flos (Kuandonghua), Belamcandae Rhizoma (Shegan), Asari Radix et Rhizoma (Xixin), Dioscoreae Rhizoma (Shanyao), Aurantii Fructus immaturus (Zhishi), Citri reticulatae Pericarpium (Chenpi), Pogostemonis Herba (Huoxiang).
|
Huashi Baidu decoction
|
New formula for COVID-19
|
ChiCTR2000030988
|
Included in guideline
|
Ephedrae Herba (Shengmahuang), Armeniacae Semen (Xingren), Gypsum fibrosum (Shengshigao), Glycyrrhizae Radix Et Rhizoma (Gancao), Pogostemonis Herba (Huoxiang), Magnoliae officinalis Cortex (Houpo), Atractylodis Rhizoma (Cangzhu), Tsaoko Fructus (Caoguo), Pinellinae Rhizoma Praeparatum (Fabanxia), Poria (Fuling), RheiRadix et Rhizoma (Shengdahuang), Astragali Radix (Shenghuangqi), Lepidii/Descurainiae Semen (Tinglizi), Paeoniae Radix rubra (Chishao).
|
Lianhua Qingwen Capsule
|
Chinese patent medicine
|
ChiCTR2000029433; ChiCTR2000029434
|
Included in guideline; used for treating H1N1 influenza
|
Forsythiae Fructus (Lianqiao), Lonicerae Japonicae Flos (Jinyinhua), Ephedrae Herba (Mahuang), Armeniacae Semen Amarum (Kuxingren), Gypsum Fibrosum (Shigao), Isatidis Radix (Banlangen), Dryopteridis Crassirhizomatis Rhizome (Mianmaguanzhong), Houttuyniae Herba (Yuxingcao), Pogostemonis Herba (Guanghuoxiang), Rhei Radix Et Rhizome (Dahuang), Rhodiolae Crenulatae Radix Et Rhizome (Hongjingtian), L-Menthol (Bohenao), Glycyrrhizae Radix Et Rhizoma (Gancao)
|
Xuebijing
|
Chinese herbal-derived injection
|
ChiCTR2000029381; ChiCTR2000030388
|
Included in guideline; used for treating severe community-acquired pneumonia
|
Radix Paeoniae Rubra (Chishao), Radix Angelica Sinensis (Danggui), Chuanxiong Rhizoma (Chuanxiong), Carthami Flos (Honghua), Radix Salviae Miltiorrhizae (Danshen)
|
Xiyanping
|
Chinese herbal-derived injection
|
ChiCTR2000029756, ChiCTR2000030117, ChiCTR2000030218/NCT04275388
|
Included in guideline
|
Sulfonate Andrographolide (Chuanxinlian)
|
Toujie Quwen granule
|
New formula for COVID-19
|
ChiCTR2000031089; ChiCTR2000031888
|
Evidence from case series study for treating COVID-19
|
Forsythiae Fructus (Lianqiao), Cremastrae Pseudobulbus (Shancigu), Lonicerae Japonicae Flos (Jinyinhua), Scutellariae Radix (Huangqin), Bupleuri Radix (Chaihu), Artemisiae Annuae Herba (Qinghao), Cicadae Periostracum (Chantui), Peucedani Radix (Qianhu), Fritillariae Cirrhosae Bulbus (Chuanbeimu), Mume Fructus (Wumei), Scrophulariae Radix (Xuanshen), Eupolyphaga Steleophaga (Tubiechong), Atractylodis Rhizoma (Cangzhu) Astragali Radix (Huangqi), Pseudostellariae Radix (Taizishen), Poria (Fuling)
|
Trials of treatment interventions
114 registered trials are treatment trials, including 67 RCTs, 18 CCTs, 12 single-arm studies, 10 real world clinical studies, and 7 retrospective studies. Participants in the majority of trials (91.2%, 104/114) were confirmed COVID–19 cases, while 5.3% (6/114) recruited both confirmed and suspected cases, and 3.5% (4/114) recruited only suspected cases. Suspected cases were defined as patients with a history epidemiology and clinical manifestations of COVID–19, yet to be confirmed by etiological or serological tests according to China’s guideline of COVID–19.3 The sample sizes ranged from 20 to 3,000, with the total of 28,109, average of 247 and median of 120, and the majority (94/114, 82.5%) of trials had a sample size below 300. Therapeutic interventions included herbal decoction/granules (in 52 trials), Chinese patent medicines (22), herbal-derived injections (12), acupuncture/ acupoint stimulation (4), TCM exercise (Daoyin, Qigong, Liuzijue, Baduanjin) (5), and TCM psychological intervention (1). The remaining trials did not report details of the interventions. Eight trials used TCM interventions alone in the treatment group, while the remaining used a combination of TCM and WM, and the same WM interventions were used in the control group. Outcome measures used the treatment trials are shown in Figure 2.
Amongst the 114 trials, six Chinese patent medicines, formulae and injections in 20 trials might be worthy of attention due to the comprehensive consideration of their availability, previous evidence, current clinical application and study progress, and inclusion by the national guidelines. The background and protocol information are as follows:
(1) Qingfei Paidu decoction (清肺排毒汤, QFPD): It was recommended by China’s guideline for treating COVID–19 at mild, moderate, severe, and critical stages since February 7, 2020 [17]. Six registered trials evaluated the effect of QFPD: One (ChiCTR2000030810) was a registered RCT comparing QFPD versus WM with sample size of 100; one (ChiCTR2000029778) was a controlled clinical trial comparing QFPD plus WM versus WM with sample size of 600; Three (ChiCTR2000030864,ChiCTR2000030883, and ChiCTR2000032767) were single-arm studies; one (ChiCTR2000030806) was a retrospective study evaluating the effectiveness of QFPD plus ulinastatin, a human urinary trypsin inhibitor. According to preliminary statistics on national data [18], 1265 confirmed cases in 10 provinces were treated with QFPD decoction up to March 23, 2020, none of mild or moderate patients converted to severe or critical stage, 98% of cases had been cured and discharged.
(2) Huashi Baidu decoction/granule (化湿败毒汤, HSBD): It was formulated by the national medical team of TCM in Hubei and recommended by the national guideline (7th version) for treating severe COVID–19 [3]. One RCT (ChiCTR2000030988) with sample size of 204 evaluated the effectiveness of HSBD granule comparing with WM. Besides, three clinical studies on HSBD had been carried out in Jinyintan Hospital (75 severe cases), Dongxihu Fangcang Hospital (124 moderate cases), and Jiangjunlu Street Health Center (894 mild and moderate cases), respectively. The results showed significant improvement in CT images of lungs and symptoms, reduction in the time of hospitalization and rate of viral clearance on PCR, and no adverse events or liver and kidney damage were found [19]. The clinical registration information on the three trials has not been found on the trial registry platforms, a RCT (ChiCTR2000030288) undertaken by Huang Luqi to evaluate the effect of a TCM formula (without name and details) for treating severe COVID–19 in Jinyintan Hospital might related to the above three trials, so it is also worthy of attention.
(3) Lianhua Qingwen Capsule (连花清瘟胶囊, LHQW) is a Chinese patent medicine developed in 2003 for treating SARS, and also showed a similar therapeutic effectiveness reduction of the duration of illness and duration of viral shedding compared with Oseltamivir in the treatment of influenza A (H1N1) virus infection [20], and was safer and cheaper than Oseltamivir [21]. A newly study showed that it exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV–2) [22]. LHQW was recommended by the national guideline (from the 4th version) for treating COVID–19 [3]. Two multicenter RCTs (ChiCTR2000029433 and ChiCTR2000029434) evaluated the effectiveness of LHQW plus WM versus exclusive WM on 240 suspected cases and 240 confirmed cases, respectively. The results of one study (ChiCTR2000029434) were firstly revealed by Zhong Nanshan, leader of the study, China’s top respiratory expert when he shared COVID–19 experience with medics overseas on a live program held by China Global Television Network in April 16, 2020. Comparing with control group, LHQW group showed higher overall recovery rate (91.5% vs. 82.4, P = 0.022), faster symptom recovery (median: 7 vs. 10d, P<0.001), and higher rate of improvement in chest CT manifestations (83.8% vs. 64.1%, P = 0.017) in mild and moderate COVID–19 patients [23]. Recruitments to the two trials has been completed.
(4) Xuebijing injection (血必净注射液): Its efficacy in treating patients with severe community-acquired pneumonia was demonstrated by a multicenter randomized placebo control trial published in Critical Care Medicine in 2019 [24]. It was recommended by the national guideline (from the 4th version) for treating severe COVID–19 [3]. Two trials evaluated the effectiveness of Xuebijing in the treatment of severe patients with COVID–19. A multicenter controlled clinical trial (ChiCTR2000029381) compared Xuebijing with WM in 400 patients; the RCT (ChiCTR2000030388) compared Xuebijing plus WM with WM in 60 patients. In the first study (ChiCTR2000029381), Xuebijing inhibited the cytokine storm and controlled the progress of severe or critical COVID–19 during the ongoing clinical trial [19].
(5) Xiyanping injection (喜炎平注射液) was recommended by the national guideline (from the 5th version) for treating COVID–19 [3]. Four RCTs (ChiCTR2000029756, ChiCTR2000030117, ChiCTR2000030218/NCT04275388, and ChiCTR2000032412) evaluated the effectiveness of xiyanping plus WM (Lopinavir / ritonavir, alpha-interferon) versus WM on mild or moderate cases, and their sample sizes were 238, 80, 348, and 426 respectively. It should be noted that ChiCTR2000030218 and NCT04275388 are probably the same study due to the same applicant, study period, design, sample size, and interventions.
(6) Toujie Quwen granule (透解祛瘟颗粒, TJQW), formulated by Guangzhou Eight People’s Hospital, has been used for treating COVID–19 in several hospitals of Guangdong province [25]. Two multicenter controlled studies (CCT: ChiCTR2000031089; RCT: ChiCTR2000031888) evaluated the effectiveness of Toujie Quwen granule plus basic treatment versus basic treatment with or without antiviral therapy for moderate or mild patients. A previous case series study involving 121 non-severe patients found that the proportion of patients with improved symptoms and/or chest CT manifestations improvements ranged from 71%~84% after taking TJQW for six days [25].
(7) TCM individualized treatment in the real world A RCT (ChiCTR2000029763) evaluated TCM treatment on moderate patients with COVID–19 in a mobile cabin hospital (known as Fangcang shelter hospital [9]). Another RCT (ChiCTR2000029601) evaluated TCM treatment based on individual syndrome differentiation on 400 cases of suspected patients. According to a recent report, intervention of CHM decoctions on suspected patients in community promoted by Prof. Tong Xiaolin, the chief investigator of study ChiCTR2000029601, significantly reduced the infection rate of suspected patients and prevented the mild/moderate patients from progression; none of the 564 mild/moderate patients in Jiangxia TCM Fangcang Hospital converted to severe [26]. Therefore, these two trials could represent the effect of individualized CHM in the real world treatment of suspected, mild and moderate patients to a certain degree, and worthy of attention.
The details of the above interventions and trials are shown in Table 3.
Trials of rehabilitation inventions
23 registered trials are rehabilitation trials, including 18 RCTs, two CCTs, and three single-arm studies. Participants were cured and discharged patients with negative results of nucleic acid PCR tests. The total sample size is 5080, with ranging from 28 to 1500, average of 221, and median of 120. TCM rehabilitation interventions included Chinese patent medicines, herbal decoction, moxibustion, and TCM exercise (Tai Chi, Liuzijue, Qigong, Baduancao). Outcome indexes included aerobic exercise capacity measured by the six-minute walk test, quality of life, positive conversion rate tested by PCR, and chest CT manifestations. Amongst the interventions evaluated in the 23 trials, moxibustion, Tai Chi, and Liuzijue were recommended by China’s rehabilitation guideline for cured COVID–19 patients [27]. Two TCM interventions were worthy of attention due to their availability and study design.
(1) Tai Chi (太极拳): it is a kind of traditional Chinese shadow boxing. Patients with moderate COVID–19 were trained in Tai Chi by TCM doctors in some mobile cabin hospitals in Wuhan, Hubei province of China. A RCT ( ChiCTR2000029460) involving 100 cured cases with viral clearance on PCR after treatment evaluated the effect of Tai Chi plus conventional rehabilitation therapy versus conventional rehabilitation therapy on the lung function and quality of life.
(2) Liuzijue (六字诀) is a traditional breathing training exercise of Qigong in TCM. A previous study found that Liuzijue promoted functional capacity of lung and quality of life in older adults with chronic obstructive pulmonary disease (COPD) at 6 months and was a good alternative home exercise program for older adults in the rehabilitation of COPD [28]. A RCT (ChiCTR2000030933) evaluated the effectiveness of Liuzijue compared with respiratory muscle training for respiratory function in 108 COVID–19 patients who had been cured and discharged. Maximal inspiratory pressure, 6-minute walking test, activities of daily living and scale of lung function were measured.